Sbds Deficient Neutrophils Exhibit Normal Numbers, Chemotaxis and Phagocytic Functions, but Impaired NADPH Oxidase Activity.
Bibliographic record
Abstract
Abstract Shwachman-Diamond syndrome (SDS) is a recessive disease with multi-system involvement, and is characterized by hematological dysfunction, exocrine pancreatic insufficiency and skeletal abnormalities. Recurrent infections are a major cause of morbidity for SDS patients, due to neutropenia and proposed defects in neutrophil functions. SDS is caused by mutations in SBDS, a highly conserved gene that has been suggested to be involved in RNA metabolism and/or ribosome biogenesis. A conditional Cre-Lox Sbds allele was generated in the mouse using gene targeting technology, as complete ablation of Sbds has been shown to lead to early embryonic lethality. To investigate neutrophil functions and their specific sensitivity to loss of Sbds, we elected to delete the gene by breeding mice with the conditional allele to mice with Cre recombinase under the control of the lysozyme M promoter. While Sbds was confirmed to be ablated in mature neutrophils in adult offspring mice, their numbers and morphology were found to be normal in peripheral blood. Sbds-ablated neutrophils were also found to have normal chemotatic and chemokinetic abilities, and they demonstrated phagocytic function comparable to neutrophils of control mice. In contrast, NADPH oxidase activity was observed to be greatly reduced in response to phorbol-12-myristate 13-acetate stimulation, while the expression levels and phosphorylation of the NADPH oxidase complex components remained intact. To evaluate the net effect of the loss of Sbds in vivo, clearance of Pseudomonas aeruginosa from infected lungs was investigated, and found to be significantly reduced in mice with Sbds-abated neutrophils compared their wild type littermates. In summary, loss of Sbds does not to affect total peripheral neutrophil numbers directly, or chemotaxis and phagocytic abilities, but was essential for a robust NADPH oxidase response. These findings suggest that neutrophils are compromised with loss of Sbds, but that at least some of the neutrophil deficiencies of SDS patients are likely due to microenvironment deficiencies, or early hematopoiesis abnormalities.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".